Molecular docking analysis of p53 with Toll-like receptors

P53 is one of the most important proteins for its role in cellular signal transduction pathways. It regulates a wide variety of cellular processes, which includes apoptosis, senescence, cell cycle arrest, differentiation, and DNA repair and replication and cancer dynamics. It is a transcription factor for various cellular proteins. Recent report suggests that P53 is linked with transduction proteins involved in cellular immunity. Toll like receptors are needed for communication in cellular immunity. The interaction between p53 and toll like receptors is reported in various studies. Therefore, it is of interest to document the molecular docking analysis of p53 with Toll-like receptors for further consideration in therapeutic development. In the present paper we studied molecular interaction between p53 and toll like receptors using molecular docking approach. We used open-source tools for molecular docking and analyzing the data. Our molecular docking results suggest there is a promising interaction between p53 and toll like receptors. Our study will be a very useful for molecular therapeutics and drug design strategies. Further, molecular dynamics studies can be useful to determine of the stability of complex form by p53 and toll like receptors.

©Biomedical Informatics (2021) associated molecular pattern). TLRs belong to the family of pattern recognition receptors (PRRs) [6,8,9]. TLRs also participate in signaling of various metabolic pathways linked to apoptosis and suppression of cancer progression [10]. However, the interaction between TLRs and p53 is known [11] with molecular interaction data [12]. Therefore, it is of interest to document the molecular docking analysis of p53 with Toll-like receptors for further consideration in therapeutic development.

Material and Methods:
P53 structure data (PDB ID: 2OCJ) was downloaded from RCSB [https://www.rcsb.org/]. We used discovery studio suit for the removal of unnecessary molecules from PDB structure file. Similarly, we also downloaded PDB structure for all human TLRs   [16]. The output of the SPSERVER has been tabled in table 3. Various statistical parameters were used such as Pair, Ecomb, Es3dc, Elocal, E3dc, E3d, Zpair, Zecomb, Zes3dc, Zelocal and Ze3dc, to find out the stable complex forming. We also used RStudio statistical package to pot heatmap for the protein-protein interaction between p53 and TLRs.

Results:
We have shown p53 and TLRs interaction obtained from HADDOCK docking in Figure 1. It is noticed that that all the TLR protein interact with p53 protein. We observed hydrogen as well as electrostatic bond near the interface between p53 and each TRL as shown in Figure 1. It is found that among all interaction between protein-protein, TLR 4 interaction is stable as shown table 1 and table  2. The binding affinity between TLR4 and p53 was found to be -18.8, which is comparatively higher among all interactions. Further, dissociation constant is also comparatively higher for p53 and TLR4 interaction. The higher is the stability constant (dissociation constant), higher is the stability of the complex. Molecular docking results using PyDOCK (online server for protein-protein docking) as shown in figure 2. It is noticed from results shown in figure 2 that there is comparatively strong interaction between p53-TLR4, p53-TLR7, p53-TLR8 and p53-TLR9.
We assessed the stability of the complex formation between p53 and various TLRs proteins using SPSERVER statistical tools as shown in figure 3. We observed that all TLR proteins forms stable complex with p53. Moreover, it is also noticed that from results shown in figure 3 that there is comparatively strong stability between p53-TLR4, p53-TLR7, p53-TLR8 and p53-TLR9 complexes. Heatmap plot, as shown in figure 4, further confirmed the interaction between p53 and TLRs are very prominent. Moreover, it is again noticed that there is comparatively strong stability between p53-TLR4, p53-TLR7, p53-TLR8 and p53-TLR9 complexes. . Docking between p53 (in blue colour) and TLR 1 (in yellow colour) (B). Docking between p53 (in blue colour) and TLR 2 (in yellow colour) (C). Docking between p53 (in blue colour) and TLR 3 (in yellow colour) (D). Docking between p53 (in blue colour) and TLR 4 (in yellow colour) (E). Docking between p53 (in blue colour) and TLR 5 (in yellow colour) (F). Docking between p53 (in blue colour) and TLR 6 (in yellow colour) (G). Docking between p53 (in blue colour) and TLR 7 (in yellow colour) (H). Docking between p53 (in blue colour) and TLR 8 (in yellow colour) (I). Docking between p53 (in blue colour) and TLR 9 (in yellow colour) (J). Docking between p53 (in blue colour) and TLR 10 (in yellow colour).

Discussion:
The role of p53 in apoptosis and cancer is reported in various research literatures [1,2,17,20, 21]. Moreover, the role of p53 in cellular immunity is still a challenging area of the research [3,4,22]. Similarly, the role of TLRs is very much studied in cellular immunity [23][24][25][26][27]. However, role of TLRs in apoptosis and cancer is still few reported [10,[28][29][30][31]. Docking result suggests that there are strong possibilities of interaction between p53 and TLRs proteins. The HADDOCK docking results in figure  1, suggests that TLR1 to TLR10 proteins interacts with p53 protein. Again, the binding affinity and dissociation constant as shown in table 1 further support the docking results obtained from HADDOCK. The PRODIGY analysis suggests that comparatively strong interaction between p53-TLR4, p53-TLR7, p53-TLR8 and p53-TLR9 complexes. Moreover, PyDock server docking results further suggest that there are interactions between p53 and TLRs proteins as shown in figure 2. The statistical assessment of the stability of complexs between p53 and various TLRs proteins also suggests and support the docking results as shown in figure3. Moreover, statistical analysis results also suggest that there is comparatively strong stability between p53-TLR4, p53-TLR7, p53-TLR8 and p53-TLR9 complexes. Finally, Heatmap plot as shown in figure 4, clarify the interactions between p53 and TLRs proteins. Heatmap plot also suggests that there is comparatively strong stable complex between p53-TLR4, p53-TLR7, p53-TLR8 and p53-TLR9.

Figure4:
Heatmap plot for interaction between p53 and TLRs. Red colour indicating strong interaction and yellow colour indicating least interaction.

Conclusions:
We document the Molecular docking analysis of p53 with Tolllike receptors. Moreover, the interaction between p53-TLR4, p53-TLR7, p53-TLR8 and p53-TLR9 is found to be stable for the understanding of their molecular mechanism. Our study will be a very useful for molecular therapeutics and drug design studies for cellular immunity and cancer. In future path, for more clarity, molecular dynamics studies can be useful to determine of the stability of complex form by p53 and toll like receptors.